We are investigating the influence of steric hindrance, random collisions, and local aromatic and ionic neighbors of cysteines on the rates of reactions of those cysteines in disulfide exchange equilibria. Spectroscopic techniques are used to obtain physical constants characterizing reactions between cysteine-containing fragments derived from commercially available proteins. The objective is to develop strategies for designing polypeptide sequences whose cysteines will direct folding into specific disulfide-crosslinked mainframes of predetermined topology. Such mainframes might serve as support for functional groups capable of rendering inhibitory activity against physiologically significant enzymes and receptors.